Molecular mechanisms of lung disease in ataxia telangiectasia

项目总结 共济失调-毛细血管扩张症(A-T)是一种罕见的常染色体隐性遗传性人类疾病，以小脑为特征 共济失调、免疫缺陷、癌症易感性、反复鼻窦肺部感染和慢性间质 肺部疾病。这种儿童疾病的预后很差，大多数患者无法存活到超过 十几岁。A-T最令人衰弱的特征是进行性神经变性；然而，除了癌症之外， 导致发病率和死亡率的主要原因之一是呼吸系统疾病，包括间质性肺。 疾病(ILD)。尽管ILD作为A-T患者的死亡原因普遍存在，但其潜在的机制 导致这种表型的原因还不是很清楚。A-T基因突变，共济失调-毛细血管扩张突变 (ATM)，已被鉴定并编码一个大的丝氨酸-苏氨酸蛋白激酶。自动取款机被认为是“大师” 控制细胞对DNA双链断裂的反应，是激活细胞周期所必需的 检查点、直接DNA修复事件和/或细胞凋亡。自动柜员机也在控制 氧化应激和ATM缺乏导致高活性氧物种水平增加以及 抗氧化剂系统的缺陷。因此，在A-T患者中观察到的多效性表型，包括ILD，是 假设是由于对DNA损伤的缺陷反应和/或累积的后果 突变细胞的氧化损伤。 这项建议的总体目标是阐明潜在的细胞和分子机制。 A-T患者的ILD，并确定预防或有效治疗这一潜在致命疾病的潜在治疗方法 疾病表型。为了实现这些目标，我们提出了以下目标：(1)开发和表征一个 A-TILD小鼠模型的建立 动物。我们已经产生了一个条件失活的ATM等位基因，可以在特定的组织中删除。 使用这个独特的模型系统，我们可以检查特定组织和细胞类型在 A-T肺病的发生和发展；(2)阐明ATM在DNA损伤反应中的作用。 肺和原代肺细胞株；以及(3)检查可能的治疗方法对肺纤维化的疗效。 A-TILD小鼠模型。总之，这些研究将为肺的病因提供重要的见解。 A-T患者的疾病，并确定潜在治疗的有效性。此外，我们的研究将 定义肺中的DNA损伤反应，发现不仅与A-T表型相关 患者，但也了解分子基础的严重肺毒性引起的一些 化疗药物。

PROJECT SUMMARY Ataxia-telangiectasia (A-T) is a rare, autosomal recessive human disorder characterized by cerebellar ataxia, immunodeficiency, cancer predisposition, recurrent sinopulmonary infections and chronic interstitial lung disease. The prognosis for this childhood disease is poor, and most patients do not survive beyond their teens. The most debilitating feature of A-T is progressive neurodegeneration; however, in addition to cancer, one of the leading causes of morbidity and mortality is respiratory system disease, including interstitial lung disease (ILD). Despite the prevalence of ILD as a cause of death in A-T patients, the underlying mechanisms that lead to this phenotype are not well understood. The gene mutated in A-T, ataxia-telangiectasia mutated (ATM), has been identified and encodes a large serine-threonine protein kinase. ATM is considered a "master controller" of cellular responses to DNA double strand breaks, and it is required for activation of cell cycle checkpoints, direct DNA repair events and/or apoptosis. ATM also plays important roles in the control of oxidative stress, and ATM deficiency leads to increased levels of highly reactive oxygen species as well as defects in antioxidant systems. Thus, the pleiotropic phenotypes observed in A-T patients, including ILD, are hypothesized to result from defective responses to DNA damage and/or the consequences of accumulated oxidative damage in mutant cells. The overall goals of this proposal are to elucidate the cellular and molecular mechanisms underlying ILD in A-T patients and to identify potential therapeutics to prevent or effectively treat this potentially fatal disease phenotype. To achieve these goals, we propose the following aims: (1) Develop and characterize a mouse model of A-T ILD using well-established and characterized methods to induce pulmonary fibrosis in animals. We have generated a conditionally inactivatable allele of ATM that can be deleted in specific tissues. Using this unique model system, we can examine the involvement of particular tissues and cell types in the initiation and progression of A-T lung disease; (2) Elucidate the roles of ATM in DNA damage responses in the lung and primary lung cell lines; and (3) Examine the efficacy of possible therapeutics on pulmonary fibrosis in the mouse model of A-T ILD. Together these studies will provide important insights into the causes of lung disease in A-T individuals and establish the effectiveness of potential treatments. In addition, our studies will define the DNA damage responses in the lung, findings that not only have relevance to phenotypes of A-T patients, but also to understanding the molecular bases underlying the severe lung toxicity caused by some chemotherapeutics.